Guanidino-heterocyclyl-phenyl-amidines and salts thereof

ABSTRACT

Compounds of the tautomeric formula ##STR1## wherein R, R 1  and R 2 , which may be identical to or different from each other, are each hydrogen or alkyl of 1 to 4 carbon atoms; 
     R 3  is straight or branched alkyl, optionally interrupted by heteroatoms such as oxygen, sulfur or nitrogen; straight or branched alkenyl; alkynyl; cyano; cycloalkyl or cycloaliphatic alkyl; a bicyclic group; aryl; or a heterocyclic group; or 
     R 2  and R 3 , together with each other and the nitrogen atoms to which they are attached, form a heterocyclic group; 
     R 4  is hydrogen, halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; and 
     Het is a substituted or unsubstituted heterocycle containing two or three heteroatoms; tautomers thereof, and non-toxic, pharmacologically acceptable acid addition salts thereof. The compounds as well as their salts are useful as anti-ulcerogenics.

This is a division of Ser. No. 465,572, filed Feb. 10, 1983, now U.S.Pat. No. 4,548,944.

This invention relates to novel guanidine-heterocyclyl-phenyl-amidinesand acid addition salts thereof, to methods of preparing thesecompounds, to pharmaceutical compositions containing them as activeingredients, and to a method using them as anti-ulcerogenics.

BACKGROUND OF THE INVENTION AND THE PRIOR ART

Histamine antagonists have been studied for many years. In the lastforty years, various substances, such as mepyramine, were found toantagonize certain effects (H₁) of histamine. These substances howeverhad no effect on gastric acid secretion which is mediated by otherhistamine receptors (H₂) [Black et al., Nature 236, 385, (1972)]. Withthe advent of cimetidine, preceded by two other compounds (burimamideand metiamide), a new type of antihistamines (H₂ -blockers) has beendiscovered which are capable of antagonizing those responses (forinstance gastric acid secretion) which are unaffected by classicalantihistamines (H₁ -blockers). More recently, new H₂ -receptorantagonists, that is, ranitidine [Bradshaw et al., Brit. J. Pharmacol.66, 464 P, (1979)], tiotidine [P. O. Jellin, Life Sci., 25, 2001,(1979)] and BL 6341 [Cavanagh et al., Fed. Proc., 40, 2652, (1981)],have been reported to be more potent than cimetidine, both as H₂-receptor antagonists "in vitro" and as inhibitors of gastric acidsecretion "in vivo".

All of these compounds share a common feature, namely a methylthioethylside-chain (--CH₂ SCH₂ CH₂ --) bearing neutral polar groups connectingbasic or basic-substituted heterocyclic rings.

In our Italian Patent Application Ser. No. 26323 A/80 we have describeda new type of H₂ -receptor antagonists, that is,imidazolyl-phenyl-amidines, which are potent H₂ -receptor antagonistsand inhibitors of gastric acid secretion. With respect to cimetidine,the imidazole ring is retained in these compounds, whereas themethyl-thioethyl side-chain is replaced by a phenyl ring connected to anamidino group.

DESCRIPTION OF THE INVENTION

More particularly, the present invention relates to a novel class ofcompounds represented by the formula ##STR2## wherein

R, R₁ and R₂, which may be identical to or different from each other,are each hydrogen or alkyl of 1 to 4 carbon atoms;

R₃ is straight or branched alkyl, optionally interrupted by heteroatomssuch as oxygen, sulfur or nitrogen; straight or branched alkenyl;alkynyl; cyano; cycloalkyl or cycloaliphatic alkyl; a bicyclic group;aryl; or a heterocyclic group; or

R₂ and R₃, together with each other and the nitrogen atom to which theyare attached, form a heterocyclic group;

R₄ is hydrogen, halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to4 carbon atoms; and

Het is a substituted or unsubstituted heterocycle containing two orthree heteroatoms; tautomers thereof, and non-toxic, pharmacologicallyacceptable acid addition salts thereof.

The dotted lines in the amidine moiety of formula I indicate twotautomeric forms, namely ##STR3##

Although the double bonds in the other moieties have been shown inparticular positions, other tautomeric forms are possible, and thepresent invention includes such tautomeric forms within its scope, bothin terms of the compounds of the invention and in terms of the processesfor their preparation.

When, in the compounds of the formula I, R, R₁ and/or R₂ are alkylgroups of 1 to 4 carbon atoms, these may, for example, be methyl orethyl; in particular, with the proviso that when R₁ is present, R₂ isabsent and vice-versa; when R₃ is a straight or branched alkyl group itmay, for example, be an alkyl group containing from 1 to 8 carbon atomswhich may optionally contain an oxygen atom, such as methoxyethyl orhydroxypropyl; a sulfur atom, such as methylthioethyl; or a nitrogenatom, such as cyanoethyl; when R₃ is a straight or branched alkenylgroup it may, for example, be an alkenyl group containing from 3 to 5carbon atoms; when R₃ represents an alkynyl group it may, for example,be an alkynyl group containing 3 or 4 carbon atoms; when R₃ is abicyclic group it may, for example, be a terpenyl bicyclic group, suchas a norbornyl group; when R₃ represents an aryl group it may, forexample, be a phenyl group; when R₃ represents a cycloalkyl orcycloaliphatic alkyl group it may, for example, contain from 3 to 6carbon atoms; when R₃ represents a heterocyclic group it may, forexample, be an unsaturated six-membered ring, such as pyridyl; when R₃and R₂, together with the adjacent nitrogen atom represent aheterocyclic group this may, for example, be a saturated five orsix-membered ring which may contain a further heteroatom, such aspyrrolidine or morpholine; when R₄ represents an alkyl or alkoxy grouphaving 1 to 4 carbon atoms it may, for example, be methyl or methoxy;when R₄ represents a halogen atom it may, for example, be a chlorineatom; when Het represents a substituted or unsubstituted heterocyclicgroup containing two or three heteroatoms it may, for example, be afive-membered ring, such as a thiazole, oxazole, 1,3,4-thiadiazole,1,2,4-thiadiazole or 1,2,4-oxadiazole ring. In the above-mentionedformula the amidine radical may be in the ortho-, meta- or para-positionon the benzene ring with respect to the Het group, and the group R₄ maybe in any position on the benzene ring.

Preferred compounds according to the present invention are those whereinthe amidine radical is in the meta-position on the benzene ring, R, R₁and R₄ are hydrogen, R₂ is absent, R₃ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, neopentyl, n-hexyl, n-octyl,allyl, dimethylallyl, propargyl, cyclopropylmethyl, cyc-hexyl,norbornyl, phenyl, pyridyl, hydroxypropyl, methoxyethyl, methylthioethylor cyanoethyl, Het is thiazolyl or 1,2,4-thiadiazolyl, and theirphysiologically compatible acid addition salts. Such compounds generallyhave better activity and are therefore preferred asantisecretory-antiulcerogenic agents and for the treatment of disordersof the gastro-intestinal tract.

The compounds of the formula I may, for example, be prepared by thefollowing methods which constitute further features of the invention.

Method A

Reaction of a guanidino-heterocyclyl-phenylamine of the formula ##STR4##in which R, R₁, R₄ and Het have the meanings previously defined, with areactive derivative of a carboxamide of the formula ##STR5## where R₃has the meanings previously defined, and A represents a lower alkoxygroup such as methoxy or ethoxy. The reaction is generally carried outat a temperature from 0° to 100° C., preferably from 20° to 60° C. Thereaction is advantageously carried out in the presence of an inertorganic solvent, for example in an alcohol having from 1 to 3 carbonatoms such as methanol or ethanol, a halogenated hydrocarbon such asdichloromethane, or in dioxane or acetone.

The starting compounds of the formula III may be prepared byconventional methods, that is, reacting an amine of the formula ##STR6##wherein R₂ and R₃ have the meanings previously defined, with a compoundof the formula ##STR7## wherein Y is a lower alkyl group, such as methylor ethyl, in the presence of a mineral acid.

Method B

Reaction of an N,N-disubstituted carboxamide dialkyl acetal of theformula ##STR8## in which R₂, R₃ and Y have the meanings previouslydefined, with an amine of the formula II. The reaction is carried out ata temperature from 20° to 80° C., and by distilling off the alcoholformed by the reaction.

Method C

Reaction of a novel N,N'-disubstituted amidine of the formula ##STR9##wherein R, R₁, R₄ and Het have the meanings previously defined, and B isa leaving group such as cyano, acetyl, carbethoxy or carbamyl, with anamine of the formula IV.

The reaction is advantageously performed in the presence of water or ofan inert organic solvent, for example a lower alcohol such as methanolor ethanol, formamide, dimethylformamide, dioxane or acetonitrile. Thereaction is generally carried out at a temperature from 10° to 50° C.,preferably at room temperature.

The starting compounds of the formulas VIIa and VIIb are obtained bymethods described in the literature, for example by reacting an amine ofthe formula II with an N-substituted alkyl imidate of the formula##STR10## in which Y and B have the meanings previously defined, oroptionally, when B in the compounds of the formulas VIIa and VIIbrepresents a cyano group, the reaction may also be performed in a singlestep by reacting an amine of the formula II with cyanamide in thepresence of a compound of the formula V. The reaction is generallycarried out in the presence of a suitable solvent such as lower alcohol,an ether, ethyl acetate, acetonitrile or dioxane, or without a solventat a temperature from 20° to 80° C.

The compounds of the formula VIII may be prepared by conventionalmethods.

The compounds of the formula I are basic and therefore form acidaddition salts with inorganic or organic acids. Examples of non-toxic,pharmacologically acceptable acid addition salts are those formed withhydrochloric acid, nitric acid, sulfuric acid, maleic acid, fumaricacid, citric acid, tartaric acid or the like by conventional methods,such as by reacting the free base with a solution of the correspondingacid in a suitable solvent. Particularly preferred acids arehydrochloric, sulfuric, maleic and fumaric acid.

Particularly preferred compounds of the present invention are thefollowing:

N-Methyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-Ethyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-Propyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-Isopropyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-Butyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-sec.Butyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-Isobutyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-Allyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-Propargyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-(2-Methoxyethyl)-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-(3-Hydroxypropyl)-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,

N-Ethyl-N'-[3-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl]-formamidine,

and their non-toxic, pharmacologically acceptable acid addition salts.

The following examples illustrate the present invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the invention is not limited to the particularexamples given below.

Preparation of starting compounds:

EXAMPLE 1 Ethyl N-[3-(2-bromo-acetyl)-phenyl]-carbamate

24.1 gm of bromine were added slowly over a period of 30 minutes to astirred suspension of 28.5 gm of ethyl N-(3-acetyl-phenyl)-carbamate in13.3 gm of dry dioxane and 245 ml of dry ether. After stirring thereaction solution for 2 hours more, it was cooled, and the product whichcrystallized out was collected and washed with ether, yielding 38.5 gmof the title compound, m.p. 108°-110° C.

EXAMPLE 2 Ethyl N-[3-(2-guanidino-4-thiazolyl)-phenyl]-carbamatehydrobromide

A mixture of 17.17 gm of ethyl N-[3-(2-bromoacetyl)-phenyl]-carbamate,7.1 gm of amidinothiourea and 45 ml of ethanol was refluxed for 4 hoursand then cooled to room temperature. The precipitate formed thereby wasfiltered off and washed with cold ethanol, yielding 22 gm of the titlecompound, m.p. 240°-2° C.

Following the above procedure, using the appropriate bromoacetylstarting materials, the following carbamates were also prepared:

Ethyl N-[4-(2-guanidino-4-thiazolyl)-phenyl]-carbamate hydrobromide,m.p. 254° C. (dec.), and

Ethyl N-[3-(2-methylguanidino-4-thiazolyl)-phenyl]-carbamatehydrobromide, m.p. 231°-233° C.

EXAMPLE 3 2-Guanidino-4-(3-aminophenyl)thiazole

A mixture of 47.1 gm of ethylN-[3-(2-guanidino-4-thiazolyl)-phenyl]-carbamate hydrobromide, 210 ml ofethanol and 210 ml of a 50% potassium hydroxide solution was refluxedfor 15 minutes. After cooling, the white precipitate which had formedwas filtered off, dissolved in water and carefully acidified withhydrochloric acid. The resulting solution was made alkaline with anexcess of sodium hydroxide solution, and the precipitate formed therebywas filtered off, washed with water and dried, yielding 20 gm of thetitle compound, m.p. 222°-224° C.

Following the above procedure, using the appropriate carbamate startingmaterial, the following thiazoles were also prepared:

(a) 2-Guanidino-4-(4-amino-phenyl)thiazole, m.p. 251°-253° C.

(b) 2-(2-Methyl-guanidino)-4-(3-amino-phenyl)-thiazole, m.p. 180°-182°C.

Preparation of end products of the formula I:

EXAMPLE 4 N-Cyano-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

(a) A solution of 9.33 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole and3.93 gm of ethyl N-cyano-formamidate in 65 ml of ethanol was stirred atroom temperature overnight. The crystalline product which separated outwas collected by filtration, washed with cold ethanol and dried,yielding 9.2 gm of the title compound, m.p. 215° C. (dec.)

(b) A mixture of 23.3 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole,18.5 gm of ethyl ortoformate and 4.2 gm of cyanamide was heated at 120°C. for 15 minutes, cooled to room temperature, treated with ethanol andfiltered, yielding 23 gm of the title compound, m.p. 214°-216° C.(dec.).

Following the above procedures, using the appropriate amine startingmaterial, the following N-cyano-amidines were also prepared:

(c) N-Cyano-N'-[4-(2-guanidino-4-thiazolyl)-phenyl]-formamidine, m.p.240° C. (dec.);

(d) N-Cyano-N'-[2-(2-guanidino-4-thiazolyl)-phenyl]-formamidine, m.p.174° C. (dec.);

(e) N-Cyano-N'-[3-(2-methyl-guanidino-4-thiazolyl)-phenyl]-formamidine,m.p. 218°-220° C.

(f)N-Cyano-N'-methyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,m.p. 216°-217° C. (dec.);

(g)N-Cyano-N'-[3-(2-guanidino-5-methyl-4-thiazolyl)-phenyl]-formamidine,m.p. 180° C., (dec.);

(h)N-Cyano-N'-[6-methyl-3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,m.p. 245°-248° C.;

(i)N-Cyano-N'-[6-chloro-3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,m.p. 265°-267° C., (dec.);

(j)N-Cyano-N'-[6-methoxy-3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,m.p. 248°-250° C. (dec.);

(k)N-Cyano-N'-[4-(2-guanidino-1,3,4-thiadiazol-5-yl)-phenyl]-formamidine,m.p. 248°-250° C. (dec.);

(l)N-Cyano-N'-[3-(2-guanidino-1,3,4-thiadiazol-5-yl)-phenyl]-formamidine,m.p. 259°-261° C. (dec.);

(m)N-Cyano-N'-[3-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl]-formamidine,m.p. 265°-268° C. (dec.);

(n)N-Cyano-N'-[4-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl]-formamidine,m.p. 253°-255° C. (dec.);

(o) N-Cyano-N'-[3-(2-guanidino-4-oxazolyl)-phenyl]-formamidine, m.p.225°-226° C.;

(p) N-Cyano-N'-[4-(2-guanidino-4-oxazolyl)-phenyl]-formamidine, m.p.222°-223° C.;

(q)N-Cyano-N'-[4-(5-guanidino-1,2,4-oxadiazol-3-yl)-phenyl]-formamidine,m.p. >270° C.; and

(r)N-Cyano-N'-[3-(5-guanidino-1,2,4-oxadiazol-3-yl)-phenyl]-formamidine,m.p. 246°-248° C.

Preparation of starting compounds:

EXAMPLE 5 5-Guanidino-3-(3-nitrophenyl)1,2,4-oxadiazole

7.3 gm of guanidine hydrochloride were added in portions to a solutionof 1.8 gm of sodium in 100 ml of ethanol. After 30 minutes of stirring,22.5 gm of 3-(3-nitro-phenyl)-5-trichloromethyl-1,2,4-oxadiazole wereadded. The solid which separated out overnight was filtered off anddried, yielding 15.2 gm of the title compound, m.p. 290°-291° C.

EXAMPLE 6 2-Guanidino-4-(4-nitro-phenyl)-oxazole hydrochloride

A solution of 90 gm of 4-nitro-phenacyl acetate and 33.9 gm of1-cyano-guanidine in 200 ml of dioxane and 20 ml of 5N hydrochloric acidwas stirred for 2 days at room temperature. A first crop of the productwas filtered off; the solution, after the addition of another 40 ml of5N hydrochloric acid, was stirred for 3 days and furnished a second cropof the product. The total yield of the title compound was 46 gm,m.p. >285° C.

EXAMPLE 7 2-Guanidino-4-(2-nitro-phenyl)-thiazole

A solution of 16.5 gm of 2-nitro-phenacyl bromide and 7.98 gm ofamidinothiourea in 70 ml of dimethylformamide was stirred at roomtemperature for 16 hours, and then poured into 350 ml of water. Thesolution was made alkaline with 10% sodium hydroxide, and the solidwhich separated out after cooling was filtered, washed with water anddried, yielding 16.9 gm of the title compound, m.p. 176°-178° C.

Following the above procedure, using the appropriate phenacyl bromide asstarting material, the following nitrophenyl-thiazole derivatives werealso prepared:

(a) 2-Guanidino-4-(4-methyl-3-nitro-phenyl)-thiazole, m.p. 225°-227° C.;

(b) 2-Guanidino-4-(4-chloro-3-nitro-phenyl)-thiazole, m.p. 248°-250° C.;and

(c) 2-Guanidino-4-(4-methoxy-3-nitro-phenyl)-thiazole, m.p. 236°-238° C.

EXAMPLE 8 2-Guanidino-4-(2-amino-phenyl)-thiazole

A solution of 57 gm of sodium sulfide octahydrate in 400 ml of methanoland 120 ml of water was added dropwise over a period of 300 minutes to ahot (60° C.) solution of 16.9 gm of2-guanidino-4-(2-nitro-phenyl)-thiazole in 120 ml of methanol. After anadditional 2 hours of heating at 60° C., the solution was filtered withcharcoal and evaporated to dryness. The residual solid was suspended inwater, filtered off and dried, yielding 12.4 gm of the title compound,m.p. 198°-200° C.

Following the above procedure, using the appropriate nitrophenylderivative, the following aminophenyl derivatives were also prepared:

(a) 2-Guanidino-4-(3-amino-4-methyl-phenyl)-thiazole, m.p. 251°-252° C.;

(b) 2-Guanidino-4-(3-amino-4-chloro-phenyl)-thiazole, m.p. 245°-248° C.;

(c) 2-Guanidino-4-(3-amino-4-methoxy-phenyl)-thiazole, m.p. 157°-159°C.;

(d) 2-Guanidino-5-(4-amino-phenyl)-1,3,4-thiadiazole, m.p. 274°-275° C.;

(e) 2-Guanidino-5-(3-amino-phenyl)-1,3,4-thiadiazole, m.p. 244°-247° C.;

(f) 5-Guanidino-3-(4-amino-phenyl)-1,2,4-thiadiazole, m.p. 282°-284° C.(as hydrochloride);

(g) 2-Guanidino-4-(4-amino-phenyl)-oxazole, m.p. 212°-213° C.;

(h) 5-Guanidino-3-(4-amino-phenyl)-1,2,4-oxadiazole, m.p. 245° C.(dec.); and

(i) 5-Guanidino-3-(3-amino-phenyl)-1,2,4-oxadiazole, m.p. 260° C.(dec.).

EXAMPLE 9 2-Guanidino-5-(4-nitro-phenyl)-1,3,4-thiadiazole

24.13 gm of guanidine nitrate were added in small portions over a periodof 30 minutes to 6.5 gm of a 50% sodium hydride oil dispersion in 200 mlof dimethylformamide. After the evolution of hydrogen has ceased, asolution 15.8 gm of 2-chloro-5-(4-nitro-phenyl)-1,3,4-thiadiazole in 300ml of dimethylformamide was added dropwise to the mixture, which wasthen stirred at room temperature for 2 hours, and then at 90° C. for 30minutes. After cooling and dilution with water, the precipitate formedthereby was filtered off and dissolved in ethanol. Hydrogen chloride wasadded to this solution, and the hydrochloride which separated out wasfiltered off and dissolved in water, and the aqueous solution was madealkaline with 10% sodium hydroxide. The free base was filtered off,washed with water and dried, yielding 9.5 gm of the title compound, m.p.295°-297° C.

Following the above procedure, using the appropriate thiadiazolederivative as starting material, the following compounds were alsoprepared:

(a) 2-Guanidino-5-(3-nitro-phenyl)-1,3,4-thiadiazole, m.p. 296°-298° C.;and

(b) 5-Guanidino-3-(4-nitro-phenyl)-1,2,4-thiadiazole, m.p. 272°-275° C.

EXAMPLE 10 2-Chloro-5-(3-nitro-phenyl)-1,3,4-thiadiazole

A mixture of 14.8 gm of 2-amino-5-(3-nitro-phenyl)-1,3,4-thiadiazole and20.67 gm of sodium nitrite was added to 25% hydrochloric acid (120 ml),cooled at -10° C. and containing a small amount of Cu powder over aperiod of 20 minutes.

The resulting solution was stirred at -5° C. for one hour and at roomtemperature for 90 minutes and was then neutralized with 10% sodiumhydroxide. After addition of sodium metabisulfite solution, the mixturewas heated at 60° C. for 10 minutes, filtered, and the solid wasextracted with chloroform. The organic solution was evaporated todryness, yielding 12 gm of the title compound, m.p. 162°-165° C.

EXAMPLE 11 5-Chloro-3-(4-nitro-phenyl)-1,2,4-thiadiazole

A solution of 75.6 gm of sodium hydroxide in 100 ml of water was addedto a stirred mixture of 101.4 gm of p-nitrobenzamidine hydrochloride, 70gm of perchloromethyl mercaptan and 760 ml of dichloromethane, whilekeeping the temperature below -5° C. After additional 2 hours at -5° C.,the resulting suspension was filtered, and the organic phase wasseparated, evaporated to dryness, and the residual solid wasrecrystallized from 95% ethanol, yielding 45 gm of the title compound,m.p. 143°-145° C.

EXAMPLE 12 3-Methylamino-phenacyl bromide hydrobromide

(a) 3-Acetylphenyliminotriphenyl phosphorane

A mixture of 67.6 gm of 3-amino acetophenone, 101.2 gm of triethylamineand 100 ml of carbon tetrachloride was added to a stirred suspension of211 gm of triphenylphosphine dibromide in 1700 ml of carbontetrachloride. After 20 minutes of refluxing, the mixture was filteredand evaporated to dryness. The residual solid was treated withisopropanol, filtered and dried, yielding 140.2 gm of the titlecompound, m.p. 135°-136° C.

(b) [N-Methyl-N-(3-acetyl-phenyl)-amino]-triphenyl phosphonium iodide

A solution of 140.2 gm of 3-acetylphenyliminotriphenyl phosphorane and56.9 gm of methyl iodide in 525 ml of dry benzene was refluxed for 8hours in an atmosphere of nitrogen. The mixture was cooled, and theprecipitate was filtered off, washed with benzene and dried, yielding120 gm of the title compound, m.p. 178°-180° C.

(c) 3-Methylamino-acetophenone

A mixture of 120 gm of [N-methyl-N-(3-acetylphenyl)-amino]-triphenylphosphonium iodide and 2250 ml of 2N sodium hydroxide was refluxed forone hour. The mixture was then cooled, acidified with hydrochloric acid,and extracted with dichloromethane. The aqueous solution was madestrongly alkaline with sodium hydroxide solution, and the amine whichseparated out was extracted with diethyl ether. After removal of thesolvent, the residue was distilled, yielding 25 gm of the titlecompound, b.p. 102°-103° C. (0.05 mmHg).

(d) 3-Methylamino-phenacyl bromide hydrobromide

A solution of 26.8 gm of bromine in 20 ml of glacial acetate acid wasadded to a solution of 25 gm of 3-methyl-amino-acetophenone and 16.1 gmof methanesulfonic acid in 200 ml of glacial acetic acid. After 12 hoursof stirring with ultraviolet light irradiation, the mixture was treatedwith 30 ml of a solution of 30% anhydrous hydrogen bromide in aceticacid, and then diluted with about 5 vol. of ether. The precipitate wasfiltered off, washed with ether and recrystallized from absoluteethanol, yielding 20 gm of the title compound, m.p. 174°-176° c. (dec.).

EXAMPLE 13 2-Guanidino-4-(3-methylamino-phenyl)-thiazole

A mixture of 20 gm of 3-methylamino phenacyl bromide hydrobromide, 7.65gm of amidinothiourea and 100 ml of ethanol was refluxed for 4 hours,and then cooled to room temperature. The dihydrobromide which separatedout was filtered off, dissolved in water, and the solution was madealkaline with 10% sodium hydroxide. The free base was collected anddried, yielding 11.5 gm of the title compound, m.p. 198°-200° C.

Preparation of end products of the formula I:

EXAMPLE 14 N-Methyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

4 gm of N-cyano-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine wereadded all at once to 40 ml of 35% methylamine in water (40 ml). A fewminutes later, the reaction product separated out of the solution. Thissolid was filtered, washed with water and dried, yielding 2.66 gm of thetitle compound.

Maleate salt (ethanol): M.p. 182° C. (dec.).

Analysis: C₂₀ H₂₂ N₆ O₈ S. Found %: C 46.98; H 4.32; N 16.41. Calc. %: C47.43; H.4.38; N 16.59.

The following compounds were prepared in analogous manner, starting fromthe above N-cyano-formamidine derivative.

(a) N-Ethyl-N'-[3-(2-guanidino-4-thiazolyl)phenyl]-formamidine

Maleate salt, (ethanol): M.p. 175°-177° C. (dec.).

Analysis: C₂₁ H₂₄ N₆ O₈ S. Found %: C 47.95; H 4.70; N 15.98. Calc. %: C48.46; H 4.65; N 16.14.

(b) N-Propyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 180° C. (dec.).

Analysis: C₂₂ H₂₆ N₆ O₈ S. Found %: C 49.43; H 4.88; N 15.59. Calc. %: C49.43; H 4.90; N 15.72.

(c) N-Isopropyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Citrate salt (ethanol): M.p. 135° C. (dec.).

Analysis: C₄₆ H₆₀ N₁₂ O₂₁ S₂. Found %: C 46.96; H 5.18; N 14.32. Calc.%: C 46.78; H 5.12; N 14.23.

(d) N-Butyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 196° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₈ S. Found %: C 49.86; H 5.03; N 15.21. Calc. %: C50.36; H 5.14; N 15.32.

(e) N-sec.Butyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 190° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₈ S. Found %: C 49.81; H 5.18; N 15.02. Calc. %: C50.36; H 5.14; N 15.32.

(f) N-Isobutyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 208° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₈ S. Found %: C 50.16; H 5.16; N 15.33. Calc %: C50.36; H 5.14; N 15.32.

(g) N-Neopentyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 187°-190° C. (dec.).

Analysis: C₂₄ H₃₀ N₆ O₈ S. Found %: C 50.73; H 5.33; N 14.81. Calc. %: C51.24; H 5.37; N 14.94.

(h) N-Hexyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 196° C. (dec.).

Analysis: C₂₅ H₃₂ N₆ O₈ S. Found %: C 51.71; H 5.65; N 14.70. Calc. %: C52.07; H 5.59; N 14.57.

(i) N-Octyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 177°-180° C. (dec.).

Analysis: C₂₇ H₃₆ N₆ O₈ S. Found %: C 53.15; H 6.00; N 13.86. Calc. %: C53.63; H 6.00; N 13.89.

(j) N-Allyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 168°-170° C. (dec.).

Analysis: C₂₂ H₂₄ N₆ O₈ S. Found %: C 49.19; H 4.47; N 15.50. Calc. %: C49.62; H 4.54; N 15.78.

(k) N-Dimethylallyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 163° C. (dec.).

Analysis: C₂₄ H₂₈ N₆ O₈ S. Found %: C 51.12; H 4.98; N 14.64. Calc. %: C51.42; H 5.03; N 14.99.

(l) N-Propargyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 170° C. (dec.).

Analysis: C₂₂ H₂₂ N₆ O₈ S. Found %: H 49.06; H 4.12; N 15.89. Calc. %: C49.81; H 4.18; N 15.84.

(m)N-Cyclopropylmethyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 183°-185° C. (dec.).

Analysis: C₂₃ H₂₆ N₆ O₈ S. Found %: C 49.82; H 4.71; N 15.28. Calc. %: C50.54; H 4.79; N 15.38.

(n) N-Cyclohexyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 190° C. (dec.).

Analysis: C₂₅ H₃₀ N₆ O₈ S. Found %: C 52.00; H 5.34; N 14.81. Calc. %: C52.26; H 5.26; N 14.63.

(o) N-Norbornyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 196° C. (dec.).

Analysis: C₂₆ H₃₀ N₆ O₈ S. Found %: C 53.15; H 5.22; N 14.21. Calc. %: C53.23; H 5.15; N 14.33.

(p)N-(2-Methoxy-ethyl)-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 182°-184° C. (dec.).

Analysis: C₂₂ H₂₆ N₆ O₉ S. Found %: C 47.67; H 4.71; N 15.15. Calc. %: C48.00; H 4.76; N 15.26.

(q)N-(2-Methylthio-ethyl)-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 180°-183° C. (dec.).

Analysis: C₂₂ H₂₆ N₆ O₈ S₂. Found %: C 46.13; H 4.57; N 14.71. Calc. %:C 46.63; H 4.62; N 14.83.

(r)N-(2-Cyano-ethyl)-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 160°-164° C. (dec.).

Analysis: C₂₂ H₂₃ N₇ O₈ S. Found %: C 48.03; H 4.16; N 18.15. Calc. %: C48.44; H 4.25; N 17.97.

(s)N-(3-Hydroxy-propyl)-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 184° C. (dec.).

Analysis: C₂₂ H₂₆ N₆ O₉ S. Found %: C 47.08; H 4.57; N 16.95. Calc. %: C46.98; H 4.66; N 17.06.

(t) N-Methyl-N'-[4-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Hydrochloride salt (ethanol): M.p. 264° C. (dec.).

Analysis C₁₂ H₁₆ Cl₂ N₆ S. Found %: C 41.25; H 4.55; N 24.31. Calc. %: C41.50; H 4.64; N 24.20.

(u) N-Ethyl-N'-[4-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Fumarate salt (ethanol): M.p. 136° C. (dec.).

Analysis: C₂₁ H₂₄ N₆ O₈ S. Found %: C 48.37; H 4.85; N 16.16. Calc. %: C48.46; H 4.65; N 16.14.

(v) N-Isopropyl-N'-[4-(2-guanidino-4-thiazolyl)-phenyl]-formamidine,m.p. 249°-250° C. (dec.).

Analysis: C₁₄ H₁₈ N₆ S. Found %: C 56.07; H 6.04; N 27.32. Calc. %: C55.61; H 6.00; N 27.79.

(w) N-Ethyl-N'-[2-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Tartrate salt (ethanol): M.p. 110° C. (dec.).

Analysis: C₃₈ H₅₀ N₁₂ O₁₈ S₂. Found %: C 44.03; H 5.14; N 16.67. Calc.%: C 44.44; H 4.91; N 16.36.

(x) N-Propyl-N'-[2-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Tartrate salt (ethanol); M.p. 135° C. (dec.).

Analysis: C₄₀ H₅₄ N₁₂ O₁₈ S₂. Found %: C 45.53; H 5.20; N 15.70. Calc.%: C 45.53; H 5.16; N 15.93.

(y) N-Allyl-N'-[2-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Tartrate salt (ethanol) M.p. 120° C. (dec.).

Analysis: C₄₀ H₅₀ N₁₂ O₁₈ S₂. Found %: C 45.51; H 4.68; N 16.12. Calc.%: C 45.71; H 4.79; N 15.99.

(z) N-Ethyl-N'-[3-(2-methylguanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 183° C. (dec.).

Analysis: C₂₂ H₂₆ N₆ O₈ S. Found %: C 49.12; H 4.94; N 15.59. Calc. %: C49.43; H 4.90; N 15.72.

(aa) N-Propyl-N'-[3-(2-methylguanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 172° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₈ S. Found %: C 50.51; H 5.11; N 15.45. Calc. %: C50.36; H 5.14; N 15.32.

(ab)N-Isopropyl-N'-[3-(2-methylguanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 95° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₈ S. Found %: C 50.25; H 5.16; N 15.10. Calc. %: C50.36; H 5.14; N 15.32.

(ac) N,N-Dimethyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 216° C. (dec.).

Analysis: C₂₁ H₂₄ N₆ O₈ S. Found %: C 48.61; H 4.70; N 16.26. Calc. %: C46.46; H 4.65; N 16.15.

(ad) N,N-Diethyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 190°-193° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₈ S. Found %: C 49.99; H 5.06; N 15.32. Calc. %: C50.36; H 5.14; N 15.32.

(ae) N-[3-(2-guanidino-4-thiazolyl)-phenyl]-1-pyrrolidinylmethanimine

Maleate salt (ethanol): M.p. 197°-199° C. (dec.).

Analysis: C₂₃ H₂₆ N₆ O₈ S. Found %: C 50.87; H 4.86; N 15.08. Calc. %: C50.54; H 4.79; N 15.38.

(af) N-[3-(2-guanidino-4-thiazolyl)-phenyl]-4-morpholinylmethanimine

Maleate salt (ethanol): M.p. 208°-210° C. (dec.).

Analysis: C₂₃ H₂₆ N₆ O₉ S. Found %: C 48.88; H 4.70; N 15.05. Calc. %: C49.10; H 4.66; N 14.94.

(ag)N-Propyl-N'-methyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 105°-106° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₈ S. Found %: C 50.21; H 4.99; N 15.45. Calc. %: C50.36; H 5.14; N 15.32.

(ah)N-Ethyl-N'-[3-(2-guanidino-5-methyl-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 155° C. (dec.).

Analysis: C₂₂ H₂₆ N₆ O₈ S. Found %: C 49.19; H 4.82; N 15.43. Calc. %: C49.43; H 4.90; N 15.72.

(ai)N-Propyl-N'-[3-(2-guanidino-5-methyl-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 160° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₈ S. Found %: C 49.86; H 4.93; N 15.32. Calc. %: C50.36; H 5.14; N 15.32.

(aj)N-Propyl-N'-[6-methyl-3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 204°-207° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₅. Found %: C 50.00; H 5.25; N 15.45. Calc. %: C50.36; H 5.15; N 15.32.

(ak)N-Propyl-N'-[6-chloro-3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 192°-195° C. (dec.).

Analysis: C₂₂ H₂₅ ClN₆ O₈ S. Found %: C 46.74; H 4.51; N 14.54. Calc. %:C 46.44; H 4.43; N 14.77.

(al)N-Propyl-N'-[6-methoxy-3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 201°-204° C. (dec.).

Analysis: C₂₃ H₂₈ N₆ O₉ S. Found %: C 49.19; H 5.07; N 14.74. Calc. %: C48.93; H 4.99; N 14.89.

(am)N-Ethyl-N'-[4-(2-guanidino-1,3,4-thiadiazol-5-yl)-phenyl]-formamidine

Maleate salt (acetone): M.p. 182°-183° C. (dec.).

Analysis: C₂₀ H₂₃ N₇ O₈ S. Found %: C 46.18; H 4.49; N 18.70. Calc. %: C46.06; H 4.45; N 18.80.

(an)N-Isopropyl-N'-[4-(2-guanidino-1,3,4-thiadiazol-5-yl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 178° C. (dec.).

Analysis: C₂₁ H₂₅ N₇ O₈ S. Found %: C 46.95; H 4.77; N 18.42. Calc. %: C47.09; H 4.71; N 18.31.

(ao)N-Isopropyl-N'-[3-(2-guanidino-1,3,4-thiadiazol-5-yl)-phenyl]-formamidine

Maleate salt (acetone): M.p. 166° C. (dec.).

Analysis: C₂₁ H₂₅ N₇ O₈ S. Found %: C 46.75; H 4.68; N 18.35. Calc. %: C47.09; H 4.71; N 18.31.

(ap)N-Ethyl-N'-[3-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 173°-175° C. (dec.).

Analysis: C₂₀ H₂₃ N₇ O₈ S. Found %: C 45.92; H 4.50; N 18.69. Calc. %: C46.06; H 4.45; N 18.80.

(aq)N-Isopropyl-N'-[3-(4-guanidino-1,2,4-thiadiazol-3-yl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 157° C. (dec.).

Analysis: C₂₁ H₂₅ N₇ O₈ S. Found %: C 46.73; H 4.71; N 18.21. Calc. %: C47.09; H 4.71; N 18.31.

(ar)N-Ethyl-N'-[4-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl]-formamidine

Maleate salt (acetone): M.p. 184° C. (dec.).

Analysis: C₂₀ H₂₃ N₇ O₈ S. Found %: C 45.70; H 4.39; N 18.68. Calc. %: C46.06; H 4.45 N 18.80.

(as)N-Propyl-N'-[4-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl]-formamidine

Maleate salt (acetone): M.p. 187° C. (dec.).

Analysis: C₂₁ H₂₅ N₇ O₈ S. Found %: C 46.86; H 4.64; N 18.42. Calc. %: C47.09; H 4.71; N 18.31.

(at)N-Isopropyl-N'-[4-(5-guanidino-1,2,4-thiadiazol-3-yl)-phenyl]-formamidine

Maleate salt (acetone): M.p. 177° C. (dec.).

Analysis: C₂₁ H₂₅ N₇ O₈ S. Found %: C 46.95; H 4.66; N 18.27. Calc. %: C47.09; H 4.71; N 18.31.

(au) N-Methyl-N'-[3-(2-guanidino-4-oxazolyl)-phenyl]-formamidine

Hydrochloride salt (ethanol): M.p. 252°-253° C. (dec.).

Analysis: C₁₂ H₁₆ Cl₂ N₆ O. Found %: C 43.26; H 4.83; N 25.37. Calc. %:C 43.51; H 4.87; N 25.37.

(av) N-Ethyl-N'-[3-(2-guanidino-4-oxazolyl)-phenyl]-formamidine

Hydrochloride salt (ethanol); M.p. 254°-255° C. (dec.).

Analysis: C₁₃ H₁₈ Cl₂ N₆ O. Found %: C 44.82; H 5.15; N 24.12. Calc. %:C 45.22; H 5.22; N 24.34.

(ax) N-Hexyl-N'-[3-(2-guanidino-4-oxazolyl)-phenyl]-formamidine

Hydrochloride salt (ethanol): M.p. 237°-238° C. (dec.).

Analysis: C₁₇ H₂₆ Cl₂ N₆ O. Found %: C 50.17; H 6.57; N 21.09. Calc. %:C 50.87; H 6.53; N 20.94.

(ay) N-Methyl-N'-[4-(2-guanidino-4-oxazolyl)-phenyl]-formamidine

Hydrochloride salt (ethanol): M.p. 239°-240° C. (dec.).

Analysis: C₁₂ H₁₆ Cl₂ N₆ O. Found: C 43.25; H 4.87; N 24.91. Calc. %: C43.51; H 4.87; N 25.37.

(az) N-Propyl-N'-[4-(2-guanidino-4-oxazolyl)-phenyl]-formamidine

Hydrochloride salt (ethanol): M.p. 232°-233° C. (dec.).

Analysis: C₁₄ H₂₀ Cl₂ N₆ O. Found %: C 47.02; H 5.58; N 23.46. Calc. %:C 46.80; H 5.61; N 23.39.

(ba) N-Butyl-N'-[4-(2-guanidino-4-oxazolyl)-phenyl]-formamidine

Hydrochloride salt (ethanol): M.p. 233°-235° C. (dec.).

Analysis: C₁₅ H₂₂ Cl₂ N₆ O. Found %: C 48.41; H 5.99; N 22.14. Calc. %:C 48.26; H 5.94; N 22.52.

(bb) N-Allyl-N'-[4-(2-guanidino-4-oxazolyl)-phenyl]-formamidine

Furmarate salt (ethanol): M.p. 150°-152° C. (dec.).

Analysis: C₁₈ H₂₀ N₆ O₅. Found %: C 53.87; H 5.06; N 21.16. Calc. %: C53.09; H 5.04; N 20.99.

(bc)N-Isopropyl-N'-[4-(5-guanidino-1,2,4-oxadiazol-3-yl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 189° C. (dec.).

Analysis C₂₁ H₂₅ N₇ O₉. Found %: C 48.10; H 4.86; N 18.61. Calc %: C48.55; H 4.85; N 18.87.

(bd)N-Methyl-N'-[4-(5-guanidino-1,2,4-oxadiazol-3-yl)-phenyl]-formamidine

Furmarate salt (ethanol): M.p. 186°-187° C. (dec.).

Analysis: C₁₅ H₁₇ N₇ O₅. Found %: C 47.85; H 4.57; N 25.91. Calc. %: C48.00; H 4.57; N 26.12.

(be)N-Isopropyl-N'-[3-(5-guanidino-1,2,4-oxadiazol-3-yl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 167° C. (dec.).

Analysis: C₂₁ H₂₅ N₇ O₉. Found %: C 48.96; H 4.85; N 19.05. Calc %. C48.55; H 4.85; N 18.87.

(bf)N-Methyl-N'-[3-(5-guanidino-1,2,4-oxadiazol-3-yl)-phenyl]-formamidine

Nitrate salt (methanol): M.p. 215°-216° C. (dec.).

Analysis: C₁₁ H₁₅ N₉ O₇. Found %: C 33.97; H 3.88; N 32.58. Calc %. C34.28; H 3.92; N 32.72.

(bg) N-Allyl-N'-[3-(5-guanidino-1,2,4-oxadiazol-3yl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 160° C. (dec.).

Analysis: C₂₁ H₂₃ N₇ O₉. Found %: C 48.21; H 4.48; N 18.80. Calc. %: C48.74; H 4.47; N 18.95.

(bh)N-sec-Butyl-N'-[3-(5-guanidino-1,2,4-oxadiazol-3-yl)-phenyl]-formamidine

Maleate salt (ethanol): M.p. 170° C. (dec).

Analysis: C₂₂ H₂₇ N₇ O₉. Found %: C 49.24; H 5.18; N 18.52. Calc. %: C49.53; H 5.10; N 18.38.

EXAMPLE 15N,N-Dimethyl-N'-[3-(-guanidino-4-thiazolyl)-phenyl]-formamidine

A solution of 2.5 gm of 2-guanidino-4-(3-amino-phenyl)-thiazole in 7.5gm of N,N-dimethylformamide diethylacetal was stirred at roomtemperature for 2 days. Addition of diethyl ether precipitated a solidwhich was filtered off and dried, yielding 2.4 gm of the title compound.

Maleate salt: M.p 214°-215° C. (dec.).

The following formamidine was prepared in analogous manner, startingfrom N,N-diethylformamide diethylacetal:

(a) N,N-Diethyl-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

Maleate salt: M.p. 190°-192° C.

EXAMPLE 16N-(2-Pyridyl)-N'-[3-(2-guanidino-4-thiazolyl)-phenyl]-formamidine

5 gm of 2-guanidino-4-(3-aminophenyl)-thiazole were added to a solutionof 9.65 gm of ethyl N-(2-pyridyl)-formamidate in 120 ml of ethanol.After stirring the mixture for 90 minutes at room temperature, the solidwhich separated out was filtered off and dried, yielding 3 gm of thetitle compound, m.p. 140° C. (dec.).

Analysis: C₁₆ H₁₅ N₇ S. Found %: C 57.14; H 4.41; N 28.86. Calc. %: C56.96; H 4.48; N 29.06.

The following formamidine was prepared in analogous manner starting fromN-phenyl formamidate:

(a) N-phenyl-N'-[3-(2-guanidino-4-thiazolyl)phenyl]-formamidine.

The compounds of the present invention, that is those embraced byformula I above and their non-toxic, pharmacologically acceptable acidaddition salts, have useful pharmacodynamic properties. Moreparticularly, they exhibit gastric acid secretion inhibiting activity inwarm-blooded animals such as rats, and are therefore useful asanti-ulcerogenics.

The antagonistic activity of compounds according to the invention onhistamine H₂ -receptors is demonstrated either in vitro or in vivo bytheir inhibition of the H₂ -dependent biological effects, which includethe histamine-evoked positive chronotropic effect and thehistamine-induced gastric secretion of acid, respectively.

The inhibition of the positive chronotropic effect was investigated inisolated guinea pig atria suspended in an organ bath (50 ml) containingan oxygenated (O₂ :95%-CO₂ :5%) Krebs-Henseleit solution (pH 7.4)maintained at 32° C. The myocardial preparation, loaded with 1 gmisometric tension, was allowed to stabilize 60 minutes, and myocardialcontractions were recorded through an isometric lever connected to astrain-gauge coupler, and the instantaneous rate was monitored with acardiotachometer and a heat-writing pen recorder. After two controlresponses to histamine (10⁶ g/ml) the test compound was added to thebath at the desired final concentration and left for 30 minutes beforethe atria were again challenged with histamine. The chronotropicresponse obtained in the presence of the antagonist was then compared tothe control response to histamine, and the present reduction of thehistamine H₂ -evoked response was calculated. The average effectiveconcentration (EC₅₀) of the H₂ -antagonist was calculated by standardprocedure accroding to Dr. Waud, Analysis of dose-response curves, in"Methods in Pharmacology" vol. 3, Smooth muscle, Ed. Daniel, E. E.Paton, M., Plenum Press, New York (1975); Ash and Schild, Br. J.Pharmacol. Chemother. 27, 427-439, 1966. The following table shows theresults obtained:

                  TABLE I                                                         ______________________________________                                        In vitro inhibitory activity of histamin-induced                              tachycardia (guinea pig atria)                                                Compound of                                                                   Example        EC.sub.50 10.sup.-7 M                                          ______________________________________                                        14             3.3                                                            14(a)          5.3                                                            14(b)          2.8                                                            14(c)          2.0                                                            14(d)          5.5                                                            14(e)          3.0                                                            14(f)          12.0                                                           14(j)          3.3                                                            14(l)          31.0                                                           14(p)          4.8                                                            14(s)          2.7                                                            14(ap)         4.5                                                            CIMETIDINE     34.0                                                           ______________________________________                                    

The ability to the test compounds to inhibit histamine-induced gastricsecretion of acid was investigated after intravenous or intraduodenaladministration in stomach-perfused rats, according to Gosh and Schild,Br. J. Pharmacol. Chemother. 13, 54, (1958).

The preparation of the animals under general anesthesia (urethane, 1g/kg i.p.) and constant temperature, was achieved by inserting and tyingin place polyethyl tubes (PE 50) in the esophagus and in thepyloricantral region. After the stomach was washed to remove residual offoods, continuous perfusion of the stomach was started with saline, 0.5ml/min. (37° C.), primed by a Jobling peristaltic pump. After 30 minutesof perfusion adaptation, the stomach perfusate was collected in 30 min.samples, and titrated for acid content, expressed as μEq of NaOH 1N. Ascontrol acid; output became constant, intravenous perfusion of histamine(1 mg/kg/hr) was started and maintained throughout the experimentalperiod. After the acid secretion had reached the steadily higher level,increasing doses of the test compounds were injected intravenously inorder to obtain dose-response functions. The ED₅₀ was then calculated bystandard procedure.

The compounds tested by the afore-mentioned procedure showed a verypotent antisecretory activity when administered intravenously at orbelow 100 μg/kg.

The results are shown in the following table:

                  TABLE II                                                        ______________________________________                                        In vivo antisecretory activity of histamin-                                   induced gastric secretion (stomach-perfused rat).                             Compound of                                                                   Example       ED.sub.50 mg.kg.sup.-1 (i.v.)*                                  ______________________________________                                        14            0.020                                                           14(a)         0.013                                                           14(b)         0.019                                                           14(c)         0.035                                                           14(d)         0.073                                                           14(e)         0.041                                                           14(f)         0.082                                                           14(j)         0.020                                                           14(l)         0.074                                                           14(p)         0.050                                                           14(s)         0.028                                                           14(ap)        0.051                                                           CIMETIDINE    0.560                                                           ______________________________________                                         *The values of activity are expressed taking the compound as a base.     

The acute toxicity of the particularly preferred compounds of theformula I was approximately determined by oral administration of asingle dose to groups of 5 Swiss mice, fasted for 18 hours before thetest. The evaluation of the incidence of mortality was considered 14days after the administration. The results are shown in the followingtable, in which the values are expressed taking the compound as a base.

                  TABLE III                                                       ______________________________________                                        Compound of                                                                   Example     No. Dead/No. Treated Mice                                         ______________________________________                                        14          0/5 at 500 mg/kg                                                  14(a)       0/5 at 500 mg/kg                                                  14(b)       0/5 at 500 mg/kg                                                  14(c)       1/5 at 500 mg/kg                                                  14(d)       4/5 at 500 mg/kg                                                  14(e)       0/5 at 500 mg/kg                                                  14(f)       0/5 at 500 mg/kg                                                  14(j)       0/5 at 500 mg/kg                                                  14(l)       0/5 at 500 mg/kg                                                  14(p)       0/5 at 500 mg/kg                                                  14(s)       0/5 at 500 mg/kg                                                  14(ap)      0/5 at 500 mg/kg                                                  ______________________________________                                    

For pharmaceutical purposes the compounds of the present invention areadministered to warm-blooded animals perorally or parenterally as activeingredients in customary pharmaceutical compositions, that is,compositions consisting essentially of an inert pharmaceutical carrierand an effective amount of the active ingredient, such as tablets,coated pills, capsules, wafers, powders, solutions, suspensions,emulsions, syrups and the like. An effective amount of the compoundsaccording to the present invention is from 0.14 to 7.14 mgm/kg bodyweight, preferably 0.28 to 2.14 mgm/kg body weight.

The following examples illustrate a few pharmaceutical compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of using the invention. Theparts are parts by weight unless otherwise specified.

EXAMPLE 17 Tablets

The tablet composition is compounded from the following ingredients:

    ______________________________________                                        N--Methyl-N'--[3-(2-guanidino-4-                                                                    50 parts                                                thiazolyl)-phenyl]-formamidine                                                Lactose               217 parts                                               Corn starch           30 parts                                                Magnesium stearate     3 parts                                                Total                 300 parts                                               ______________________________________                                    

Preparation:

The active ingredient, the lactose and the corn starch are combined, andthe mixture is homogeneously moistened with water. After screening ofthe moist mass and drying in a tray dryer, the mixture is again passedthrough a screen, and the magnesium stearate is added. Then, the mixtureis compressed into tablets weighing 300 mg each. Each tablet contains 50mg of active ingredient.

EXAMPLE 18 Gelatin capsules

The capsule filler composition is compounded from the followingingredients:

    ______________________________________                                        N--Ethyl-N'--[3-(2-guanidino-4-                                                                     50 parts                                                thiazolyl)-phenyl]-formamidine                                                Corn starch          170 parts                                                Magnesium stearate    2 parts                                                 Total                222 parts                                                ______________________________________                                    

Preparation:

The active ingredient is mixed with the inert ingredients, and themixture is passed through a screen and mixed homogeneously in a suitabledevice. The resulting mixture is filled into hard gelatin capsules (222mg per capsule); each capsule contains 50 mg of the active ingredient.

EXAMPLE 19 Injection solution

The solution is compounded from the following ingredients:

    ______________________________________                                        N--Propyl-N'--[3-(2-guanidino-4-                                                                  50 parts                                                  thiazolyl)-phenyl]-formamidine                                                Water for injection q.s. ad                                                                       5000 parts by vol.                                        ______________________________________                                    

Preparation:

The active ingredient is dissolved in the water, and the resultingsolution is filled into 5 cc-ampules under sterile conditions. Eachampule contains 50 mg of the active ingredient.

Any one of the other compounds embraced by formula I or a non-toxic,pharmacologically acceptable acid addition salt thereof may besubstituted for the particular active ingredient in Examples 17 through19. Likewise, the amount of active ingredient in these illustrativeexamples may be varied to achieve the dosage unit range set forth above,and the amounts and nature of the inert pharmaceutical carrieringredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. A compound of the formula ##STR11## wherein R and R₁ areeach independently hydrogen or alkyl or 1 to 4 carbon atoms;R₄ ishydrogen, halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4carbon atoms; B is cyano, acetyl, carbethoxy or carbamyl; and Het is athiazole, oxazole, 1,3,4-thiadiazole, 1,2,4-thiazdiazole or1,2,4-oxadiazole ring.